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Serial measurements of positron-emitting isotope activity in rat brain.
- A H Lockwood and
- P J Kenny
Stroke Volume 12, Issue 21 March 1981

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This report describes the construction and performance characteristics of a device capable of making rapid serial measurement of rat brain radioactivity following the administration of a positron emitting isotope. Two bismuth germanate oxide (BGO) scintillation detectors in a coincidence detection circuit are used to achieve the necessary degree of collimation. Data from the device can be used to characterize cerebral biochemical and physiological processes using computer-assisted mathematical models.
Noninvasive detection and quantification of left-to-right shunts in children using oxygen-15 labeled carbon dioxide.
- D M Tamer,
- D D Watson,
- P J Kenny,
- W R Janowitz,
- H Gelband and
- A J Gilson
Circulation Volume 56, Issue 41 October 1977

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A method for the detection and quantification of left-to-right intracardiac shunts is described which utilizes a single breath inhalation of oxygen-15 labeled carbon dioxide (C15O2). The inhaled gas rapidly crosses the alveolar membrane and the oxygen-15 label is exchanged through the carbonate cycle to form oxygen-15 labeled water within the pulmonary capillary blood. Pulmonary indicator clearance curves are measured by external scintillation probes. A simplified method of shunt flow quantification was developed from indicator dilution principles and used for the analysis of the clearance curves. Inhalation studies were performed with 62 children on the day prior to cardiac catheterization. The presence or absence of left-to-right shunt was confirmed by contrast angiography in all cases. Twenty-six children were found to have no shunts by C15O2 inhalation, oximetry or angiography. Of the 36 with shunts, 34 were detected by C15O2. Two of these were designated as equivocal because they were considered to be less than the threshold of definitive detection by C15O2 (having Qp/Qs less than 1.2); 32 were positive and there were two false negatives with small ventricular septal defects. There were no false positives by C15O2. The correlation coefficient between C15O2 and oximetry values of shunt flow for those patients with proven shunts was 0.82.
Effects of heart rate on ventricular size, stroke volume, and output in the normal human fetus: a prospective Doppler echocardiographic study.
- J Kenny,
- T Plappert,
- P Doubilet,
- D Salzman and
- M G Sutton
Circulation Volume 76, Issue 11 July 1987

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The effect of heart rate on cardiac output in the fetal heart is controversial. We used Doppler echocardiography to investigate the effects of increasing heart rate on stroke volume and ventricular output in the normal human fetal heart. Heart rate was increased in 25 human fetuses (mean age 36 weeks) by auditory stimulation with a sound emitter placed on the mother's abdomen. Aortic or pulmonary diameters were measured at valve level from two-dimensional echocardiographic images and cross-sectional areas were calculated. Blood flow velocity spectra from the pulmonary artery or aorta were digitized to obtain flow velocity integrals before and after auditory stimulation. Stroke volume was calculated as the product of the flow velocity integral and the area of the great vessel. Prestimulation mean heart rate was 132 +/- 8 beats/min and increased after auditory stimulation to 158 +/- 9 beats/min (p less than .001). Stroke volume decreased with the increase in heart rate from 3.7 +/- 1.4 ml before stimulation to 3.0 +/- 1.1 ml after stimulation (p less than .001), but ventricular output calculated as the product of stroke volume and heart rate remained unchanged (0.48 +/- 0.18 liter/min before vs 0.48 +/- 0.17 liter/min after stimulation). The decrease in stroke volume was accompanied by a decrease in ventricular end-diastolic area, although there was no change either in end-systolic area or fractional change in area. This study demonstrates that increases in heart rate within the physiologic range in the normal human fetus result in a decrease in ventricular size and stroke volume but no change in ventricular output or ventricular shortening.
Basal and Oxidative Stress–Induced Expression of Metallothionein Is Decreased in Ascending Aortic Aneurysms of Bicuspid Aortic Valve Patients
- Julie A. Phillippi,
- Ekaterina A. Klyachko,
- John P. Kenny,
- Michael A. Eskay,
- Robert C. Gorman and
- Thomas G. Gleason
Circulation Volume 119, Issue 1812 May 2009

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Background— Bicuspid aortic valve (BAV) is a heritable condition that has been linked by an unknown mechanism to a predisposition for ascending aortic aneurysm. Matrix metalloproteinases have been implicated in this predisposition. Metallothionein is a poorly characterized, metal-binding protein that regulates matrix metalloproteinases and is an antioxidant known to be upregulated under oxidative stress.Methods and Results— To determine putative factors involved in the pathogenesis of aortic aneurysm in BAV patients, our first goal was to identify genes that are dysregulated in ascending aortic aneurysms of BAV patients compared with tricuspid aortic valve patients and nondiseased (control) donors. By microarray analysis (22 000 probe sets), 110 dysregulated genes were identified in BAV compared with tricuspid aortic valve patients and control donors; 8 were genes of the metallothionein family. Metallothionein gene expression and protein expression were significantly lower in aortic tissue and cultured aortic smooth muscle cells from BAV patients compared with control subjects. Matrix metalloproteinase-9 expression was increased in BAV aortic samples relative to controls. BAV aorta was more susceptible to oxidative stress, and induction of metallothionein under oxidative stress was reduced in BAV patients compared with control subjects.Conclusions— These results demonstrate dysregulated metallothionein expression in ascending aortic smooth muscle cells of BAV patients that may contribute to an inadequate response to oxidative stress and provoke aneurysm formation. We hypothesize that metallothionein plays a pivotal role in the response of ascending aortic smooth muscle cells to oxidative stress cues normally involved in the maintenance of the extracellular matrix, including the regulation of matrix metalloproteinase expression.
Changes in intracardiac blood flow velocities and right and left ventricular stroke volumes with gestational age in the normal human fetus: a prospective Doppler echocardiographic study.
- J F Kenny,
- T Plappert,
- P Doubilet,
- D H Saltzman,
- M Cartier,
- L Zollars,
- G F Leatherman and
- M G St John Sutton
Circulation Volume 74, Issue 61 December 1986

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We used Doppler echocardiography to quantitate the changes in intracardiac blood flow velocities and right and left ventricular stroke volumes in 80 normal human fetuses from 19 to 40 weeks gestation. Blood flow velocity spectra across the aortic, pulmonary, tricuspid, and mitral valves were digitized to obtain peak velocities (m/sec) and flow velocity integrals. Aortic and pulmonary diameters were measured at valve level from two-dimensional echocardiographic images and cross-sectional area was calculated assuming a circular orifice. Ventricular stroke volume was calculated as the product of the cross-sectional area of a great vessel and the flow velocity integral through that vessel. The pulmonary arterial and aortic diameters increased linearly with gestational age (r = .82, r = .84), and pulmonary arterial diameter consistently exceeded aortic diameter. There was a positive relationship between stroke volume and gestational age: stroke volume increased exponentially from 0.7 ml at 20 weeks to 7.6 ml at 40 weeks for the right ventricle (r = .87) and from 0.7 ml at 20 weeks to 5.2 ml at 40 weeks for the left ventricle (r = .91). Similar results were obtained for right and left ventricular and combined cardiac outputs. In 44% of the fetuses it was possible to quantitate both right and left ventricular stroke volumes. There was a close correlation between right and left ventricular stroke volumes in these fetuses (r = .96) and right ventricular stroke volume exceeded left ventricular stroke volume by 28%.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract 2127: Metallothionein (MT) Expression Is Down-regulated and MT Induction by Oxidative Stress Is Blunted in Ascending Aortic Aneurysms in Bicuspid Aortic Valve Patients
- Ekaterina A Klyachko,
- John P Kenny,
- Robert C Gorman,
- Joseph H Gorman,
- Edwin C McGee,
- Nalini Rajamannan,
- Patrick M McCarthy and
- Thomas G Gleason
Circulation Volume 114, Issue suppl_1831 October 2006

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Background: Bicuspid aortic valve (BAV) is heritable and predisposes to ascending aortic aneurysm by an unknown mechanism. Altered oxidative stress-responses leading to matrix metalloproteinase (MMP) dysregulation has been postulated. Metallothionein (MT), a poorly characterized metal-binding protein, functions in other organs to scavenge reactive oxygen species and regulate MMPs, but has never been implicated in ascending aortic aneurysmal disease. We hypothesize that MT plays a role in regulating aortic extracellular matrix homeostasis and that perturbation of its expression promotes aortic aneurysm. In this study we sought to prove that MT expression is significantly down-regulated in the ascending aorta of BAV patients.Methods: RNA and protein were extracted from matched, unfractionated ascending aortic homogenates from normal donors and aneurysms with tricuspid aortic valve (TAV) and BAV phenotype. Microarray analysis of 50 aortic samples was performed. Altered gene expression was confirmed by RNA quantification using real-time PCR (n=44). MT protein expression was analyzed by immunoblotting–cysteine residues were modified with monobromobimane to enable more sensitive MT detection (n=78). MT induction by oxidative stress was tested in aortic smooth muscle cell (SMC) cultures (n=6).Results: Microarray analysis showed decreased expression of 104 genes of which 8 were MT isogenes among BAVs (false discovery rate <5 %.) RNA quantification analysis confirmed markedly decreased expression of the MT1A, MT1X and MT2A isoforms in BAVs compared to controls (p<0.0001). Subsequent normalized densitometry of immunoblots revealed decreased MT protein expression in BAV aortic samples {normal: 120±11.5, TAV: 108±17.2, BAV: 49.9±6.7; normal v. TAV (p=0.84), normal v. BAV (p=0.004), BAV v. TAV (p=0.002). SMC responses to oxidative stress in vitro revealed marked reduction in MT protein expression in BAVs compared to normals.Conclusion: MT expression is down-regulated in the ascending aorta of people with BAV and ascending aneurysm compared to people with tricuspid aortic valves. Normal MT induction in SMC by oxidative stress is markedly blunted in BAV aorta which may predispose to aortic aneurysmal disease.
Abstract 467: Neural Stem Cells Contribute to Peripheral Nerve Repair by Coordinated Angiogenesis and Neurogenesis
- Haruki Sekiguchi,
- Kentaro Jujo,
- Rajasingh Johnson,
- Tina Thorne,
- Andrew Scarpelli,
- Trevor Clarke,
- Aiko Ito,
- John Kenny,
- Sol Misener,
- Ekaterina Klyachko,
- Masaaki Ii and
- Douglas W Losordo
Circulation Volume 116, Issue suppl_1616 October 2007

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Background: Neural stem cells (NSC) are believed to participate in tissue repair and regeneration after injury. Recent studies have indicated that NSC can differentiate not only into neurons, but also into endothelial cells (EC), suggesting a potentially novel role for NSC in nerve recovery. In the present study, we performed experiments to explore the potential of NSC in the setting of peripheral nerve injury and to test the hypothesis that neurogenesis and vasculogenesis can cooperatively participate in nerve repair.Methods and results: NSC were isolated from Rosa 26 mice (in which all cells constitutively express b-galactosidase) and expanded ex vivo into neurospheres. Since Estradiol (E2) is known to favorably affect neovascularization after ischemic injury, E2 treatment was used to promote neovascularization. After unilateral sciatic nerve crush injury, C57/BL6 mice were randomized to one of 4 treatments: E2 administered locally via biodegradable polymer Poly Lactide-CO Glycoside (PLGA), NSC administered locally, combination of NSC and E2, or PLGA control. All treatment groups showed significant increases in intraneural angiogenesis and motor conduction velocity (MCV) ratio (P<0.05 vs. cont), with combination of NSC and E2 being the most effective treatment (P<0.05 vs. other groups). Furthermore, NSC treated animals showed higher nerve voltage amplitude (P<0.05 vs. cont and E2) indicating increased neurogenesis. NSC homing was studied in mice injected via tail vein with NSC. Immunostaining of crushed sciatic nerves showed that NSCs migrate to the injury site; moreover some NSC differentiated into EC (CD31 staining) or Schwann cells (S100 staining). Study of NSC differentiation in vitro indicated that NSC can differentiate into multiple lineages, including EC (acLDL, BS-1 lectin, eNOS, CD31 staining), and smooth muscle (α-SM actin) as well as neural lineage. In vitro, E2 promoted NSC differentiation into EC (as acLDL and BS1- lectin double positive cells).Conclusions: NSC promote angiogenesis and nerve recovery after injury. Both in vivo and in vitro experiments provide evidence that NSC can differentiate into endothelial cells. This study reveals the potential for NSCs to contribute to repair of injured peripheral nerves.
Differences in Myocardial Structure and Coronary Microvasculature Between Men and Women With Coronary Artery Disease
- Duncan J. Campbell,
- Jithendra B. Somaratne,
- Alicia J. Jenkins,
- David L. Prior,
- Michael Yii,
- James F. Kenny,
- Andrew E. Newcomb,
- Darren J. Kelly and
- Mary Jane Black
Hypertension Volume 57, Issue 21 February 2011

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Women younger than 75 years with stable angina or acute coronary syndrome have higher cardiac mortality than similarly aged men, despite less obstructive coronary artery disease. To determine whether the myocardial structure and coronary microvasculature of women differs from that of men, we performed histological analysis of biopsies from nonischemic left ventricular myocardium from 46 men and 11 women undergoing coronary artery bypass graft surgery who did not have previous cardiac surgery, myocardial infarction, heart failure, atrial fibrillation, or furosemide therapy. The 2 patient groups had similar clinical characteristics, apart from a lower body surface area (BSA) in women (P=0.0015). Women had less interstitial fibrosis than men (P=0.019) but similar perivascular fibrosis. Arteriolar wall area/circumference ratio, a measure of arteriolar wall thickness, was 47% greater in women than men (P=0.012). Cardiomyocyte width and diffusion radius were positively correlated, and capillary length density was negatively correlated with BSA (P<0.05). Whereas cardiomyocyte width, capillary length density, diffusion radius, and cardiomyocyte width/BSA ratio were similar for men and women, women had a greater diffusion radius/BSA ratio (P=0.0038) and a greater diffusion radius/cardiomyocyte width ratio (P=0.027). Women also had lower vascular endothelial growth factor (VEGF) receptor-1 levels (P=0.048) and VEGF receptor-1/VEGF-A ratio (P=0.024) in plasma. We conclude that women with extensive coronary artery disease have greater arteriolar wall thickness and diffusion radius relative to BSA and to cardiomyocyte width than men, which may predispose to myocardial ischemia. Additional studies of larger numbers of women with less extensive coronary artery disease are required to confirm these findings.
Abstract 12774: Detecting Change in Cardiopulmonary Bypass Blood Flow Rate With a Novel, Wireless, Wearable Doppler Ultrasound Patch: A Pilot Study
- Chelsea E Munding,
- Jon-Emile S. S Kenny,
- Zhen Yang,
- Geoffrey Clarke,
- Mai Elfarnawany,
- Andrew M Eibl,
- Joe K Eibl,
- Bhanu Nalla and
- Rony Atoui
Circulation Volume 146, Issue Suppl_18 November 2022

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Introduction: Assessing preload reserve (PR) is important when managing cardiac surgery patients. Typically, a 10% change in cardiac output is used as a reference standard to gauge PR; how this change in cardiac output translates to common carotid artery (CCA) velocity is unknown. In this pilot study, we compared known changes in cardiopulmonary bypass (CPB) flow rate to those measured by a novel wireless, wearable Doppler ultrasound placed over the CCA.Methods: A sample of 14 adult patients undergoing elective CABG was studied. While on CPB, at least two changes in blood flow (one negative, one positive) were made. The corresponding change in CCA velocity was measured by a wearable continuous wave (CW) Doppler ultrasound patch. For each subject, CPB flow changes were determined from the displayed spectrogram by the peristaltic pulsation frequency and CCA velocity changes were calculated from the automated maximum velocity trace. 5-10s windows pre- and post-CPB speed changes were selected, with sufficient signal quality to determine both relative CPB flow and CCA velocity. A “dose-response” curve was fitted to the relative changes in flow and velocity for each subject, as shown in Fig. 1, and the CCA velocity change corresponding to a 10% change in CPB flow was calculated.Results: CPB flows ranged from 0.5-6.3L/min. Mean relative flow changes were -58 and 179%, corresponding to mean CCA velocity changes of -43 and 107%. A mean CCA velocity change of 14% was found to correspond to 10% CPB flow change, ranging from 1.5-27.8%.Conclusions: CCA velocity measured with the Doppler patch successfully tracked changes in CPB flow. A CCA velocity change of >14% suggests a >10% change in cardiac output. Although preliminary, these results provide another important parameter for predicting the response to preload using a novel, easy-to-use, wireless Doppler device.
The renin response to aortic occlusion is enhanced by stimulation of the hypothalamus.
- J P Porter
Hypertension Volume 12, Issue 11 July 1988

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The sympathetic nervous system is an important factor that can induce increased renin secretion by the kidney. In recent years, the notion has arisen that the sympathetic nervous system may also function to set the level of responsiveness of the kidney to nonneural stimuli for renin secretion. However, evidence in favor of this possibility has come primarily from studies employing direct electrical stimulation of renal nerves, and no attempt has been made to determine if central neural sites can also influence the responsiveness of the kidney. In the present study, the ability of hypothalamic activation to enhance the renin response to suprarenal aortic occlusion was investigated. Conscious, freely moving rats with an inflatable cuff placed around the aorta were used to determine the relationship between renal-perfusion pressure and plasma renin activity in the control state and during continuous low-level stimulation of the paraventricular nucleus. The stimulation resulted in a rightward shift in the curve that related renal perfusion pressure to plasma renin activity; that is, for any given decrease in renal perfusion pressure, the plasma renin activity was greater during the ongoing stimulation. This rightward shift appeared to be mediated by increased renal nerve activity, since renal denervation prevented the shift. These data indicate that the hypothalamus, which plays an important role in regulating sympathetic activity, is capable of increasing the sensitivity of the kidney to a nonneural stimulus for renin secretion. This effect may become important in certain hypertensive and prehypertensive states where central neural activity is thought to be enhanced.
Effect of stress on the control of renin release in spontaneously hypertensive rats.
- J P Porter
Hypertension Volume 15, Issue 31 March 1990

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Recent reports suggest that centrally induced increases in sympathetic outflow to the kidney have the potential to enhance the sensitivity of pressure-dependent renin release. In the present study, the possibility was investigated that spontaneously hypertensive rats (SHR), which are thought to have increased tonic sympathetic outflow to the kidney, exhibit enhanced renin release in response to reduced renal perfusion pressure. The increase in plasma renin activity in response to a graded suprarenal aortic constriction was determined in conscious young (6-9 weeks of age) and adult (14-16 weeks of age) SHR and age-matched Wistar-Kyoto (WKY) control rats. Under conditions of relatively little stress, the renin response to reduced renal perfusion pressure was not enhanced in young or adult SHR when compared with age-matched WKY rats. That is, this regulatory mechanism was not "reset" in the hypertensive animals. When challenged with an acute stress (air to the face) both age groups of SHR exhibited a significantly enhanced response. Neither age group of WKY rats was affected by the acute air stress. These data suggest that, under unstressed conditions, pressure-dependent renin release probably does not contribute to the elevation of arterial pressure in the SHR. However, under stressful conditions, the contribution of this system may be significant. Intermittent increases in sympathetic outflow to the kidney that can occur in the SHR in response to daily stresses have the potential to render it more sensitive to spontaneous reductions in perfusion pressure. Occasional exaggerated release of renin could then contribute to the hypertensive process.
Antiarrhythmic Drug Therapy for Sustained Ventricular Arrhythmias Complicating Acute Myocardial Infarction
- Jonathan P. Piccini
Circulation Volume 120, Issue suppl_183 November 2009

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Abstract #2363Jonathan P. Piccini, Phillip J. Schulte, Karen S. Pieper, Rajendra H. Mehta, Duke Clinical Res Inst, Durham, NC; Eric J. Topol, Scripps Translational Science Inst, La Jolla, CA; Harvey D. White, Auckland City Hosp, Auckland, New Zealand; Frans Van de Werf, Univ Hosp Leuven, Leuven, Belgium; Diego Ardissino, Univ of Parma, Parma, Italy; Robert M. Califf, Christopher B. Granger, E. Magnus Ohman, John H. Alexander, Duke Clinical Res Inst, Durham, NCJonathan P. Piccini, 2009 Finalist and Presenting Author
Abstract WP90: Intraoperative Premature Rupture of Middle Cerebral Artery Aneurysms: Risk Factors and Sphenoid Ridge Proximation Sign
- Jaechan Park Park
Stroke Volume 47, Issue suppl_11 February 2016

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Object: The investigation of surgical cases of a ruptured middle cerebral artery (MCA) aneurysm to identify the risk factors of an intraoperative premature rupture.Methods: Based on an 8-year period and among 927 patients with a ruptured intracranial aneurysm, the medical records of 182 consecutive patients with a ruptured MCA aneurysm were examined for cases of a premature rupture, and the risk factors were then investigated. The considered risk factors included: the patient age, gender, WFNS clinical grade, modified Fisher grade, presence of an ICH, frontal ICH, temporal ICH, volume of the ICH, maximum diameter of the ruptured MCA aneurysm, length of the pre-aneurysmal M1 segment between the carotid bifurcation and the MCA aneurysm, and the presence of a sphenoid ridge proximation sign. The use of axial source images and a three-dimensional reconstruction of the brain CTA revealed a sphenoid ridge proximation sign based on the spatial proximation between a potential rupture point of the MCA aneurysm and the cortical arachnoid of the sphenoidal sylvian fissure, adjacent superficial sylvian veins, and the sphenoid ridge.Results: A total of 11 patients (6.0%) suffered a premature rupture of the MCA aneurysm during surgery. The premature rupture occurrences were classified according to the stage of the surgery as follows: 1) craniotomy and dural opening (n = 1), 2) aspiration or removal of the ICH (n = 1), 3) retraction of the frontal lobe (n = 1), 4) dissection of the sphenoid segment of the sylvian fissure to access the proximal vessel (n = 4), and 5) peri-aneurysmal dissection (n = 4). Univariate and multivariate analyses revealed that the presence of a sphenoid ridge proximation sign, a frontal ICH associated with the ruptured MCA aneurysm, and the length of the pre-aneurysmal M1 segment were all statistically significant risk factors for a premature rupture of a MCA aneurysm.Conclusions: Patients exhibiting a sphenoid ridge proximation sign, the presence of a frontal ICH, and/or a short pre-aneurysmal M1 segment are high-risk patients for an intraoperative premature rupture of a MCA aneurysm. Such high-risk MCA aneurysms have a superficial location close to the arachnoid in the sphenoidal compartment of the sylvian fissure and have a rupture point directing anteriorly.
Abstract 20886: Lack of Efficacy With Ranolazine in Patients Treated With Concomitant Amiodarone: Results From the RAID Trial
- Jonathan P Piccini,
- James P Daubert,
- Ignatius G Zarraga,
- Peter M Jessel,
- Karen MacMurdy,
- Merritt Raitt,
- Mark C Haigney,
- Arthur Moss and
- Wojciech Zareba
Circulation Volume 136, Issue suppl_114 November 2017

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Introduction: Patients with implantable cardioverter defibrillators (ICD) are often treated with amiodarone. We sought to determine if the efficacy of ranolazine, a late-Na current blocker therapy, differs according to amiodarone use.Methods: RAID was a double-blind, placebo- controlled clinical trial of high-risk ICD patients with nonischemic or ischemic cardiomyopathy that randomized patients to ranolazine 1,000 mg bid versus placebo. Concomitant amiodarone antiarrhythmic therapy was permitted.Results: Overall, there were 1,012 patients enrolled (mean age: 64±10 years; 18% women), among which 102 received amiodarone (52 in the placebo arm) and 908 did not receive amiodarone (450 in placebo arm). Those treated with amiodarone at baseline were more often male (92 vs 80%, p=0.004), had lower heart rate (66±12 vs 72±12 bpm, p<.001), a lower estimated glomerular filtration (63±19 vs 77±25 mL/min/1.73 m2, p<.001), were more likely to be implanted for secondary prevention ICD (43 vs 33%, p=0.037), and if implanted for primary prevention were more likely to have had prior ventricular arrhythmia (49 vs 36%, p=0.008). Within the placebo arm, amiodarone was not associated with higher or lower unadjusted rates of VT/VF (amiodarone 23% vs 29% no amiodarone, p=0.35) or the primary endpoint composite of VT/VF requiring ATP/shock or death (amiodarone 31% vs 40% no amiodarone, p=0.18). There was evidence of a potential interaction between amiodarone status and ranolazine (p=0.148) for the primary endpoint. Among those without amiodarone therapy, the primary endpoint was reduced with ranolazine (adjusted HR 0.79, 95%CI: 0.63-0.99; p=0.045). In patients taking amiodarone there was no evidence of reduction in the primary endpoint with ranolazine (adjusted HR 1.36, 95%CI: 0.68-2.74; p=0.386).Conclusions: Ranolazine led to a reduction in the occurrence of VT/VF requiring ATP or shock or death in patients who were not taking amiodarone. These benefits are not evident in patients receiving both amiodarone and ranolazine.
Role of angiotensin subtype 2 receptor in neointima formation after vascular injury.
- P Janiak,
- A Pillon,
- J F Prost and
- J P Vilaine
Hypertension Volume 20, Issue 61 December 1992

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The role of angiotensin receptor subtypes 1 and 2 was assessed on neointima formation after injury in rat carotid artery. The effects of angiotensin converting enzyme inhibition by perindopril (3 mg.kg-1 x day-1 p.o.) and selective blockade of angiotensin subtype 1 receptors by DuP 753 (5 and 30 mg.kg-1 x day-1 p.o.) were compared on proliferative response to balloon injury. In rats treated 6 days before and for 14 days after injury, perindopril significantly reduced (-76%, p < 0.01) myointimal hyperplasia. In contrast, DuP 753 at 5 mg.kg-1 x day-1 did not modify the hyperplastic response to balloon catheterization. Only at 30 mg.kg-1 x day-1 was DuP 753 able to reduce neointima formation (-47%, p < 0.05). This dose was equipotent to perindopril on the renin-angiotensin system as assessed by the pressor response to angiotensin II and angiotensin I. Therefore, blockade of subtype 1 receptors was a less effective means of suppression of myointimal growth than angiotensin converting enzyme inhibition, suggesting that another angiotensin receptor subtype or converting enzyme substrates are involved in this process. For the determination of whether angiotensin subtype 2 receptors were implicated, the specific subtype 2 receptor antagonist CGP 42112A (1 mg.kg-1 x day-1) was continuously infused perivascularly for 14 days in the vicinity of the injured carotid artery. CGP 42112A was as effective in preventing neointima formation as perindopril (-73%, p < 0.01, versus -76%, p < 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract 20837: Neurocognitive Function in Atrial Fibrillation: Catheter Ablation versus Medical Management
- Jonathan P Piccini,
- Jeffrey Browndyke,
- Mary Cooter,
- Tiffany Bisanar,
- Ashley Flynn,
- Marat Fudim,
- Nathan H Waldron,
- Mark F Newman,
- James P Daubert and
- Joseph P Mathew
Circulation Volume 136, Issue suppl_114 November 2017

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Introduction: Catheter ablation of atrial fibrillation (AF) can be complicated by cerebral microembolization. We compared neurocognitive function, intracranial white matter lesion volume and brain functional connectivity in patients undergoing AF ablation and those treated with medical therapy only.Methods: Patients undergoing AF ablation (ABL, n=12) or treated with medical therapy only (MM, n=11) were evaluated with a battery of neurocognitive tests along with structural and functional brain imaging (baseline, 6 weeks, and 1 year). Cognitive battery scores were converted into Z-scores, grouped into 4 predefined domains, and compared via t-tests or Wilcoxon rank sum tests. The association between total intracranial white matter lesion volumes (TLV) and cognitive change was assessed via Spearman correlation. Differences in the association between TLV changes and resting-state brain functional connectivity (rsFC) changes were compared between groups controlling for baseline TLV volumes.Results: Mean age was 69.7±5.0 and 78% were male. At 6 weeks, there were no significant differences between groups in the 4 cognitive domain scores. At 1 year, MM patients trended toward a decline in the attention domain score when compared to the ABL patients (ABL: 0.37±0.63; MM: -0.18±0.79; p=0.10; effect size: 0.76). At 6-weeks TLVs were not different between groups but increased from baseline to 1 year in the MM group (2.8 [0.9-8.2] to 6.1 [1.2-14.0]) and was correlated with a decline in executive function (ρ=-0.67, p=0.04) and attention (ρ=-0.55, p=0.13). There were no significant differences between groups in the association between TLV change and rsFC at 6 weeks, but the MM group demonstrated decreased right putamen rsFC from baseline to 1 year in association with TLV changes over the same period. The changes in putamen rsFC at 1-year were associated with changes in attention domain performance (R²=0.78, p=0.007).Conclusions: When compared to a medically managed control group, patients undergoing catheter ablation may experience a longer-term benefit from decreased AF-related microemboli and preservation of cognitive function. Larger, prospective studies are needed to confirm these benefits.
Abstract 255: Sex Difference of Clinical Outcomes in Patients with Out-of-Hospital Cardiopulmonary Arrest: A Prospective Multicenter Observational Study
- Tomoyoshi Tamura,
- Noritoshi Ito,
- Kei Nishiyama,
- Kei Hayashida,
- Masaru Suzuki,
- Toshiaki Mochizuki,
- Atsushi Kataoka,
- Noriaki Yamada,
- Tsuyoshi Hatada,
- Hideo Himeno,
- Masayuki Fujioka,
- Taku Oomura,
- Yukitoshi Toyoda,
- Mitsuru Abe,
- Takaya Morooka,
- Yuusuke Taniguchi,
- Shingo Hori and
Circulation Volume 128, Issue suppl_2226 November 2013

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OBJECTIVE: There is a strong interest in differences in the outcomes between men and women with out-of-hospital cardiopulmonary arrest (OHCA). The aim of this study is to examine the sex differences of clinical outcomes in patients with OHCA.METHODS: The Japan-Prediction of neurological Outcomes in patients Post cardiac arrest (J-POP) registry is a prospective, multicenter, cohort study to test whether regional cerebral oxygen saturation (rSO2) predicts neurological outcomes in OHCA. In this post-hoc analysis, OHCA were collected after excluding patients exposed to extracorporeal cardiopulmonary bypass from the J-POP registry. The primary outcome measure was a return of spontaneous circulation (ROSC) prior to hospital arrival, and secondary outcome measure was a 90-days neurological outcome.Results: Between May 2011 and July 2012, 1204 consecutive patients, age 72±15 years, 40.4% of women, were examined. Men were younger than women (70±15 vs. 75±15 years, p<0.001), with higher percentage of witness status (53.7% vs. 43.1%, p<0.001), and with higher percentage of rSO2 more than 40% at hospital arrival (12.1% vs. 7.0%, p<0.01), and tended to have higher percentage of cardiac etiology (57.6% vs. 52.4%, p=0.07). 118 (9.8%) patients achieved ROSC prior to hospital arrival. 90-day survival rate was 6.1% (n=73), and 90-day good neurological outcome rate was 3.5% (n=42). Men had higher chance of ROSC (11.7% vs. 7.0%, p<0.01), and good neurological outcome at 90 days (4.6% vs. 1.8%, p=0.01). Multivariate analysis adjusting for age (less than 75 y/o or not), witnessed, received CPR by bystander and etiology revealed that sex male was chosen as an independent predictor for ROSC prior to arrival (RR 1.59, 95%CIs 1.03-2.45). Mantel-Haenszel test adjusting for cardiac etiology also showed that men had higher rate of good neurological outcome (RR 2.47, 95%CIs 1.16-5.23).Conclusion: Our results demonstrate that men had significantly better chance of ROSC regardless of age, received BLS and etiology, and had better neurological prognosis after cardiogenic OHCA. Additional studies are needed to validate these observations for other potential genetic factors.
Response by Halcox and Wareham to Letter Regarding Article, “Assessment of Remote Heart Rhythm Sampling Using the AliveCor Heart Monitor to Screen for Atrial Fibrillation: The REHEARSE-AF Study”
- Julian P.J. Halcox and
- Kathie Wareham
Circulation Volume 137, Issue 2015 May 2018

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“Road Map” to Improving Enrollment in Cardiac Rehabilitation: Identifying Barriers and Evaluating Alternatives
Journal of the American Heart Association Volume 6, Issue 10

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Beyond the Laboratory: Clinical Implications for Statin Pleiotropy
- Julian P.J. Halcox and
- John E. Deanfield
Circulation Volume 109, Issue 21_suppl_11 June 2004

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Results from large-scale clinical trials of lipid lowering with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have led to a revolution in the management of atherosclerosis. In addition to their potent effect on serum lipid levels, statins influence several other cellular pathways, including those involving inflammatory, oxidative, and thrombotic processes. These effects clearly have the potential to beneficially modify the atherogenic process, and it has been suggested that they contribute to the impressive results seen in the clinical trials. We review the clinical evidence for benefits of statin therapy that are distinct from their effect on lipid biology. In particular, we address three key issues: the role of statins in diseases not traditionally associated with elevated cholesterol levels; whether clinical benefits are seen with statin therapy before an effect on lipid levels; and whether the magnitude of clinical benefit observed with statin therapy is unrelated to the degree of cholesterol reduction. At present, low-density–lipoprotein lowering seems to be the primary mechanism underlying the clinical benefits of statin therapy and should remain the focus of risk-reduction strategies in clinical practice.

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